Hypoglycemic 5-substituted oxazolidine-2,4-diones

ABSTRACT

Hypoglycemic 5-chromanyl, 2,3-dihydro-5-benzo[b]-furanyl, 5-pyridyl, 5-quinolyl, 5-pyrrolyl, 5-indolyl, 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl and 5-isoxazolyl oxazolidine-2,4-diones and the pharmaceutically-acceptable salts thereof; certain 3-acylated derivatives thereof; a method of treating hyperglycemic animals therewith; and intermediates useful in the preparation of said compounds.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of copending application Ser. No.783,982, filed Oct. 3,1985now U.S. Pat. No. 4,689,336, which is adivision of Ser. No. 574,236, filed Jan. 26,1984, now U.S. Pat. No.4,565,820, which is a division of application Ser. No. 380,176, which isa division of application Ser. No. 380,176 filed May 20,1982, now U.S.Pat. No. 4,431,810, which is a division of application Ser. No. 252,962,filed Apr. 4,1981, now U.S. Pat. No. 4,342,771, which

BACKGROUND OF THE INVENTION

The present invention relates to certain 5-chromanyl,2,3-dihydrobenzo[b]furanyl, 5-pyridyl, 5-quinolyl, 5-pyrrolyl,5-indolyl, 5-thiazolyl, 5-oxazolyl, 5-isothia-zolyl and 5-isoxazolylderivatives of oxazolidine-2,4dione having utility as hypoglycemicagents.

In spite of the early discovery of insulin and its subsequentwide-spread use in the treatment of diabetes, and the later discoveryand use of sulfonylureas (e.g., chlorpropamide, tolbutamide,acetohexamide, tolazamide) and biguanides (e.g., phenformin) as oralhypoglycemic agents, the treatment of diabetes remains less thansatisfactory. The use of insulin, necessary in a high percentage ofdiabetics where available synthetic hypoglycemic agents are noteffective, requires multiple daily, usually self, injection.Determination of the proper dosage of insulin requires frequentestimations of the sugar in the urine or in the blood. Theadministration of an excess dose of insulin causes hypoglycemia, witheffects ranging from mild abnormalities in blood glucose to coma, oreven death. Where effective, a synthetic hypoglycemic agent is preferredover insulin, being more convenient to administer and less prone tocause severe hypoglycemic reactions. However, the clinically availablehypoglycemics are unfortunately fraught with other toxic manifestationswhich limit their use. In any event, where one of these agents may failin an individual case, another may succeed. A continuing need forhypoglycemic agents, which may be less toxic or succeed where othersfail, is clearly evident.

In addition to the hypoglycemic agents cited above, a variety of othercompounds have been reported to possess this type of activity, asreviewed recently by Blank [Burger's Medicinal Chemistry, FourthEdition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080 ].

The oxazolidine-2,4-diones of the present invention are novel compounds;this in spite of the fact that the oxazolidine-2,4-diones are broadlyknown as a class of compounds [for an extensive review, see Clark-Lewis,Chem. Rev. 58, pp. 63-99 (1958)]. Among the compounds known in thisclass are 5-phenyloxazolidine-2,4-dione, variously reported as anintermediate to certain beta-lactam antibacterial agents (Sheehan, U.S.Pat. No. 2,721,197), as an antidepressant agent (Plotnikoff, U.S. Pat.No. 3,699,229) and as an anticonvulsant agent [Brink and Freeman, J.Neuro. Chem. 19 (7), pp. 1783-1788 (1972)]; a number of5-phenyloxazolidine-2,4-diones substituted on the phenyl ring, e.g.,5-(4- methoxyphenyl) oxazolidine-2,4-dione [King and Clark-Lewis, J.Chem. Soc., pp. 3077-3079 (1961)],5-(4-chlorophenyl)oxazolidine-2,4-dione [Najer et al., Bull. soc. chim.France, pp. 1226-1230 (1961)], 5-(4-methylphenyl) oxazolidine-2,4-dione[Reibsomer et al., J. Am. Chem. Soc. 61, pp. 3491-3493 (1939)], and5-(4-aminophenyl) oxazolidine-2,4-dione (German Patent No. 108,026); and5-(2-pyrryl)oxazolidine-2,4-dione [Ciamacian and Silber, Gazz. chim.ital. 16, 357 (1886); Ber. 19, 1708-1714 (1886)]. The last-namedcompound, having no prior known utility, shows only relatively weakhypoglycemic activity (vide post, Table I).

Oxazolidine-2,4-dione and substituted oxazolidine-2,4-diones(specifically, the 5-methyl and 5,5-dimethyl derivatives) have beenreported as acid moieties suitable for forming acid-addition salts withthe hypoglycemic, basic biguanides (Shapiro and Freedman, U.S. Pat. No.2,961,377). We have determined that neither oxazolidine-2,4-dioneitself, nor 5,5-dimethyloxazolidine -2,4-dione possess the hypoglycemicactivity of the compounds of the present invention.

Recently, a group of spiro-oxazolidine-2,4-dione derivatives have beenreported which are aldose reductase inhibitors, thus finding utility inthe treatment of certain complications of diabetes (Schnur, U.S. Pat.No. 4,200,642).

A process for the synthesis of 3-aryloxazolidine-2,4-diones (whereinsaid aryl group is 6 to 12 carbon atoms, unsubstituted or substitutedwith one or more halogen atoms, methyl or methoxy) is the subject ofanother recent U.S. Pat. (Scholz, U.S. Pat. No. 4,220,787). The utilityof these compounds is not specified.

SUMMARY OF THE INVENTION

The present invention is concerned with compounds of the formula##STR1## wherein R is hydrogen, (C_(l) -C₄)-alkanoyl (e.g., formyl,acetyl, isobutyryl), benzoyl, (C₂ -C₄)-carbalkoxy (e.g., carbomethoxy,carbethoxy, carboisopropoxy), (C₁ -C₃)-alkylcarbamoyl (e.g.,N-methylcarbamoyl, N-propylcarbamoyl), (C₅ -C₇)-cycloalkylcarbamoyl(e.g., N-cyclohexylcarbamoyl) or di-(C₁ -C₃)-dialkylcarbamoyl (e.g.,N,N-dimethylcarbamoyl); and

R¹ is: ##STR2## wherein R' is (C_(1-C) ₄)alkyl or phenyl, R" ishydrogen, (C₁ -C₄ ) alkyl or phenyl and X is halo (fluoro, chloro, bromoor iodo); these formulae are intended to emcompass 2 -or 3-pyrrolyl andindolyl derivatives, with substituents as specified; ##STR3## wherein Yis hydrogen or (C₁ -C₃) alkoxy, Y' is hydrogen or (C₁ -C₃)alkyl and Y"is hydrogen or halo; ##STR4## wherein Z' is hydrogen, halo or (C₁-C₃)alkoxy and Z" is hydrogen or halo; ##STR5## wherein W is hydrogen orhalo, and n is 1 or 2; these formula are intended to encompass 6- or7-halo-8-chromanyl or 5- or 6-halo-7-benzofuranyl derivatives; ##STR6##wherein Q is sulfur or oxygen and V is hydrogen or (C₁ -C₃) alkyl; or##STR7## wherein Q is sulfur or oxygen; and V is hydrogen or (C₁-C₃)alkyl; these formula are intended to encompass 3-, 4- and5-isothiazolyl and isoxazolyl derivatives; and pharmaceuticallyacceptable cationic salts thereof when R is hydrogen, as well as thepharmaceutically acceptable acid addition salts thereof when R¹ containsa basic nitrogen function.

It is believed that the inherent, high activity of these compoundsresides primarily in those compounds wherein R is hydrogen, and thatthose compounds wherein R is one of a variety of carbonyl derivativesdefined above represent so-called pro-drugs, i.e., the carbonyl sidechain is removed by hydrolysis under physiological conditions, yieldingthe fully-active compounds wherein R is hydrogen.

The expression "pharmaceutically acceptable cationic salts" is intendedto define such salts as the alkali metal salts, (e.g., sodium andpotassium), alkaline earth metal salts (e.g., calcium and magnesium),aluminum salts, ammonium salts, and salts with organic amines such asbenzathine (N,N'-dibenzylethylenediamine), choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), benethamine(N-benzylphenethylamine), diethylamine, piperazine, tromethamine(2-amino-2-hydroxymethyl -1,3-propanediol), procaine, etc.

The expression "pharmaceutically acceptable acid addition salts" isintended to include such salts as the hydrochloride, hydrobromide,hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate,maleate, succinate, etc.

The compounds of the present invention possess hypoglycemic activity,reflecting their clinical utility in the lowering of the blood glucoselevel of hyperglycemic mammals, including man, to normal values. Theyhave the special advantage of lowering blood glucose values to a normalrange without danger of causing hypoglycemia. The compounds of thepresent invention are tested for hypoglycemic (anti-hyperglycemic)activity in rats, using the so-called glucose tolerance test, asdescribed in greater detail hereinafter

Preferred compounds, because of their better hypoglycemic activity, arethose wherein R is hydrogen, or the pharmaceutically acceptable saltsthereof. Among those compounds of the formula (1) wherein R is hydrogen,the most preferred compounds, because of their excellent hypoglycemicactivity, are:

5 -(1-methyl-2-pyrrolyl)oxazolidine-2,4-dione;

5 -(1-ethyl-2-pyrrolyl)oxazolidine-2,4-dione;

5 -(1-phenyl-2-pyrrolyl)oxazolidine-2,4-dione;

5 -(2-methoxy-3-pyridyl)oxazolidine-2,4-dione;

5 -(2-ethoxy-3-pyridyl)oxazolidine-2,4-dione;

5 -(5-chloro-2-methoxy-3-pyridyl)oxazolidine-2,4-dione;

5 -(5-chloro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione;

5 -(8-quinolyl)oxazolidine-2,4-dione;

5 -(7-methoxy-8-quinolyl)oxazolidine-2,4-dione;

5 -(6-chloro-8-quinolyl)oxazolidine-2,4-dione;

5 -(6-fluoro-8-quinolyl)oxazolidine-2,4-dione;

5 -(2-benzthiazolyl)oxazolidine-2,4-dione;

5 -(2-thiazolyl)oxazolidine-2,4-dione;

5 -(6-chloro-8-chromanyl)oxazolidine-2,4-dione;

5 -(6-fluoro-8-chromanyl)oxazolidine-2,4-dione;

5 -(5-chloro-2,3-dihydro-7-benzofuranyl)oxazolidine-2,4-dione; and

5 -(3-methyl-5-isoxazolyl)oxazolidine-2,4-dione.

DETAILS OF THE INVENTION

The compounds of the present invention are prepared by a variety ofmethods, as summarized in Flowsheet sheet I, wherein

R¹ is as defined above;

R² is lower alkyl (e.g. methyl or ethyl);

R³ is hydrogen, lower alkyl or phenyl; and

R⁴ is hydrogen, or acyl such as acetyl or benzoyl.

A particularly convenient synthesis for compounds of the presentinvention is via carboximidate (3). The latter compound is reacted withphosgene in an inert solvent such as tetrahydrofuran in the presence of2 to 2.3 equivalents of a tertiary amine (e.g. triethylamine,N-methylmorpholine). A further equivalent of tertiary amine is used ifthe carboximidate is introduced as the acid addition salt (e.g.hydrochloride salt). The temperature of the reaction is not critical,but lower temperatures (e.g. -10° to 10° C.) are preferred during theinitial stages of the reaction, particularly if it is desired to isolatethe intermediate 4-alkoxyoxazol-2-one (4). Isolation of thisintermediate is carried out by simple evaporation of the reactionmixture to dryness. On further reaction at higher temperatures (e.g. 20°-150° C.) or on aqueous work-up the intermediate (4) is converted to thedesired oxazolidine-2,4-dione. When a primary or secondary aminefunction is desired in the final product, this functionality isintroduced via an oxazolidine-2,4-dione containing a group selectivelyreducible (e.g. by catalytic hydrogenation or acid/metal couple) to theprimary or secondary amine. For example an N-benzylindole can be used asa precursor for an indole derivative. ##STR8##

The carboximidate (3) is conveniently prepared from the correspondingaldehyde by the sequence: ##STR9##

The aldehyde (11) is converted to the cyanohydrin (13) by standardprocedures (e.g. via the bisulfite adduct, which is reacted with cyanidein a two phase, aqueous-organic solvent system). Alternatively, thealdehyde is converted to the trimethylsilyl cyanohydrin (12) by reactionwith trimethylsilylcarbonitrile in the presence of a catalytic quantityof a Lewis acid, e.g., zinc iodide. A reaction inert solvent (e.g.methylene chloride, ether) is generally used when the aldehyde is asolid, but is optional when the aldehyde is a liquid. The temperature ofthe reaction is not critical, it being conveniently made up at reducedtemperature (e.g. 0-5° C.) and allowed to proceed at room temperaturefor a matter of hours or days, as necessary to achieve completereaction. If desired, the trimethylsilyl ether can be hydrolyzed tocyanohydrin, conveniently at reduced temperature (e.g. -10° C.) in a twophase strong aqueous acid/organic solvent system.

Either the cyanohydrin (13) or the trimethylsilyl ether (12) isconverted to the carboximidate (3) by strong acid catalyzed alcoholysis(using strictly anhydrous conditions). A convenient method is to simplydissolve the nitrile in alcohol which has been saturated with hydrogenchloride) and allow the solution to stand until carboximidate formationis complete. Temperature is not critical, although lower temperatures(e.g. 0-25° C.) generally lead to more optimal yields.

The aldehydes required for the above syntheses are broadly availableeither commercially, or by literature methods. For example,N-alkylpyrrole-2-carbaldehydes are obtained by alkylation ofpyrrole-2-carbaldehyde (Weygand, Organic Preparations, Interscience, NewYork, 1945, p. 403) using conditions specifically exemplifiedhereinafter for the preparation of N-alkylpyrroles, or by Reimer-Tiemanformylation of N-alkylpyrrole (cf Weygand loc. cit.); 3-formylindolesare similarly obtained from indoles [cf Boyd and Robson, Biochem J. 29,p. 555 (1935; Shabica et al., J. Am. Chem. Soc. 68, p. 1156 (1946)]; avariety of the presently required aldehydes are further available by theRosenmund reduction of the corresponding acid chlorides, the hydrolysisof gem-dihalides, oxidation of primary alcohols, interaction of Grignardreagents with orthoformic esters and other methods known in the art.Additional methods are noted in the Preparations detailed hereinafter.

Another suitable precursor for those oxazolidine-2,4-diones of thepresent invention lacking a primary or secondary amine function is thealpha-hydroxy amide (5). The latter compound is converted to the desiredoxazolidine-2,4-dione (1), either by reaction with alkyl chloroformatein the presence of a basic catalyst such as potassium carbonate, or byreaction with a dialkyl carbonate in the presence of a more stronglybasic catalyst such as sodium methoxide or potassium tert-butoxide. Analcohol is generally suitable as solvent for the latter reaction with 1to 3 equivalents of both dialkyl carbonate and base employed, preferably2-3 equivalents of each. When a primary or secondary amine function isdesired in the final product, this functionality is introduced via anoxazolidine-2,4-dione containing a suitable precursor group, asdescribed above.

The required alpha-hydroxy amide is conveniently prepared fromcyanohydrin (13) or from alpha-hydroxy acid or ester (6): ##STR10##Convenient conditions for the hydrolysis of the cyanohydrin (13) are totreat the cyanohydrin in formic acid with excess concentratedhydrochloric acid. A temperature range of 0-75° C. is generallysatisfactory, depending upon the stability of the individual amide inthis medium. If desired, an intermediate formate ester of (5) can beisolated under these conditions. Over hydrolysis to the acid can beavoided by tlc monitoring of the reaction, as detailed below. Convenientconditions for the aminolysis of ester (6) are to simply heat the esterin hot concentrated ammonium hydroxide.

The alpha-hydroxy ester (6) itself can also be employed as the immediateprecursor of the desired oxazolidine-2,4-dione. The ester is reactedwith urea (or one of certain substituted ureas, such as phenyl urea or1-acetyl-3-methylurea) in the presence of a basic catalyst such assodium ethoxide (suitably 1 equivalent) in alcohol at a temperature of50-110° C. The ester to be used for this purpose is by no meansrestricted to a simple lower alkyl ester, but can be any one of a broadvariety of esters, e.g. phenyl, benzyl, etc. Furthermore, the ester canbe replaced by a 1,3-dioxolan -4-one, an alpha-acyloxy ester or athioester e.g., ##STR11## and the urea can be replaced by a urethan.

Two other precursors suitable for the synthesis of the desiredoxazolidine-2,4-diones are the thio compounds (7) and (8). The 2-thioxocompound (7) is converted to the desired oxazolidine-2,4-diones underoxidative conditions, e.g. mercuric ion, aqueous bromine or chlorine,metaperiodate, or aqueous hydrogen peroxide, usually in excess and inthe presence of a co-solvent, such as a lower alcohol. The temperatureof reaction is not critical, temperatures in the range 25-100° C. beinggenerally satisfactory. Other methods are usually preferred when R¹ hasan amine function, since competing oxidation at the nitrogen tends toreduce yields and complicates isolation of the desired product; it hasbeen found, however, that when the product contains a tert-amine (e.g.,pyridine, quinoline), that periodate or bromine are reagents well-suitedfor this purpose. The oxazolidine-2,4-diones are obtained from thealkylthio compounds (8) by simple acid or base catalyzed hydrolysis.Preferable conditions are aqueous hydrochloric acid in a temperaturerange of 0-50° C.

The precursor 2-thioxo compound (7) is prepared from the correspondingaldehyde (11), generally accomplished in an aqueous acidic media by theaction of thiocyanate (1-1.1 equivalents) and cyanide (1 to 1.2equivalents) at 0-70° C., following the method of Lindberg and Pedersonby which method the preparation of 5-(2-thienyl)-2-thiooxazolidin-4-onehas been reported [Acta Pharm. Suecica 5 (1), pp. 15-22 (1968); Chem.Abstr. 69, 52050k]. The precursor 2-alkylthio compounds (8) can beprepared by alkylation of the 2-thioxo compounds (7), e.g. with an alkylhalide or dialkyl sulfate, preferably in the presence of at least twoequivalents of a base such as a lower alkoxide in a reaction inertsolvent such as a lower alkanol. The 3-alkyl derivative can be aby-product of this reaction.

Also suitable as a precuror is the 2-imino-oxazolidine -4-one derivative(9), readily hydrolyzed to the oxazolidine-2,4-dione, preferably underaqueous acid conditions. The required 2-iminooxazolidin-4-one isobtained by condensation of the alpha-hydroxy ester (6) with guanidineor with thiourea in the presence of one equivalent of a strong base suchas sodium alkoxide, by ammonolysis of the 2-alkoxy compound (isomericwith 4) or the 2-thioalkyl compound (8), by alkali induced cyclizationof the appropriate alpha-halogenureides (R¹ CHZCONHCONHR³ wherein Z is ahalogen such as chloro or bromo), or by the condensation of theappropriate alkyl alpha-haloacetates (R¹ CHZCOOR²) with urea or asubstituted urea (R³ NHCONH₂).

Ammonolysis of the 4-alkoxy derivatives (4) yields 4-imino derivatives(isomeric with 9). The latter compounds are also readily hydrolyzed tooxazolidine -2,4-diones. The 4-alkoxy derivatives themselves are alsoprepared from the silver salt of the desired oxazolidine-2,4-dione.

Also highly useful as precursors of the oxazolidine -2,4-diones of thepresent invention are the dialuric acids and acyl dialuric acids (10).These are readily converted, under mildly basic conditions, to thedesired oxazolidine-2,4-diones. Methods suitable for the preparation ofprecursor dialuric acids (10) are shown in Flowsheet II, wherein thesubstituents R¹, R² and R⁴ are as defined above, and M is Li, MgC1,MgBr, MgI, or other suitable metal.

A general method for preparing dialuric acids appropriate as precursorsof the oxazolidine-2,4-diones of the present invention is from themalonic ester derivatives (14), involving the two stages of basecatalyzed condensation with urea and oxidation to the hydroxy or acyloxycompound. When the first stage is oxidation, the intermediate is aso-called tartronic acid derivative (15), while when the first stage iscondensation, the intermediate is a so-called barbituric acid (16). WhenR¹ contains an amine function (e.g. 2-aminophenyl), it is preferred tocarry out oxidation as the first stage, preventing possiblecomplications of nitrogen oxidation. When condensation is the secondstage, the dialuric acid is usually not isolated, at least in pure form,and is further converted, under basic conditions of the condensation, tothe oxazolidine-2,4-dione. ##STR12##

The substituted malonic esters required for the above syntheses, whennot available commercially, are obtained by literature methods, such asalcoholysis of alpha-cyano esters [cf. Steele, J. Am. Chem. Soc. 53, 286(1931)], carbalkoxylation of esters [cf. Horning and Finelli, Org.Syntheses 30, 43 (1950)]and decarbonylation of alpha-keto estersobtained by the condensation of dialkyl oxalate with carboxylate esters[Reichstein and Morsman, Helv. Chim. Acta 17, 1123 (1934); Blicke andZienty, J. Am Chem. Soc. 63, 2946 (1941)].

A less general method for the preparation of the appropriate dialuricacid intermediate is to react an electron rich heteroaryl/aryl compound,e.g., ##STR13##

Now available is yet another method for the preparation of certaindialuric acid intermediates. This method, preferred when the appropriatestarting materials are readily available, involves the reaction ofalloxan (preferably in anhydrous form) with the appropriate organometalderivative (e.g., organolithium, Grignard reagent). For example:##STR14## Protection strategies are required when using this method forpreparation of certain oxazolidine-2,4-diones wherein R¹ carries asubstituent which is not compatible with organometallic reactions, e.g.,an acyl group is protected as its ethylenic ketal. In other cases, suchas when R¹ carries a group such as nitro or amino, this method generallylacks utility.

It will be evident to those skilled in the art that the preferredprocess for the oxazolidine-2,4-diones of the present invention willvary from one given value of R¹ to another, depending upon such factorsas availability of starting materials, yields, ability to removeundesirable impurities from the end-products, the chemical nature of thesubstituent groups contained in the final products, etc.

The pharmaceutically-acceptable cationic salts of the compounds of thepresent invention which form such salts are readily prepared by reactingthe acid forms with an appropriate base, usually one equivalent, in aco-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodiumethoxide, sodium hydride, potassium methoxide, magnesium hydroxide,calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine,meglumine, benethamine, diethylamine, piperazine and tromethamine. Thosesalts which do not precipitate directly are isolated by concentration todryness or by addition of a non-solvent. In some cases, salts can beprepared by mixing a solution of the acid with a solution of a differentsalt of the cation (sodium ethylhexanoate, magnesium oleate), employinga solvent in which the desired cationic salt precipitates, or can beotherwise isolated by concentration and addition of a non-solvent.

The pharmaceutically acceptable acid addition salts of the compounds ofthe present invention which form such salts are readily prepared byreacting the base forms with an appropriate acid, usually oneequivalent, in a cosolvent. Typical acids are hydrochloric, hydrobromic,nitric, sulfuric, phosphoric, methanesulfonic, maleic, succinic, etc.Those salts which do not precipitate directly are isolated byconcentration to dryness or by addition of a non-solvent.

3-Acylated derivatives of the present invention are readily prepared byusing standard conditions of acylation, e.g. the reaction of theoxazolidine-2,4-dione salt (per se, or conveniently formed in situ bythe addition of one equivalent of a tertiary amine such as triethylamineor N-methylmorpholine with an equivalent of the appropriate acidchloride or acid anhydride) or reaction of the oxazolidine-2,4-dionewith the appropriate organic isocyanate, optionally in the presence of acatalytic amount of tertiary amine base. In either case, the reaction iscarried out in a reaction inert solvent, such as toluene,tetrahydrofuran or methylene chloride. The temperature is not critical,and can be over a broad range (e.g. 0-150° C.). It will be evident tothose skilled in the art that such acylation will be complicated bycompeting or even selective sidechain (R¹) acylation when the sidechaincontains a primary or secondary amine function.

It will be evident to those skilled in the art that the compounds of thepresent invention are asymmetric and therefore capable of existing intwo optically active enantiomeric forms. The racemic compounds of thepresent invention, being acids when R is H, form salts with organicamines. These racemic forms are therefore generally capable ofresolution into the optically active forms by the classic method offorming diastereomeric salts with optically active amines, now separableby selective crystallization; alternatively those compounds containing abasic amine function can be resolved by forming a salt with an opticallyactive acid, preferrably a strong organic acid such as a sulfonic acid.In general, one of the enantiomeric forms is found to have greateractivity than the other.

The reactions employed to prepare the compounds of this invention cangenerally be monitored by standard tlc methods, employing commerciallyavailable plates. Suitable eluants are common solvents such aschloroform, ethyl acetate or hexane or suitable combinations thereofwhich will differentiate starting materials, products, by-products, andin some cases intermediates. Applying these methods, which are wellknown in the art, will permit further improvement in the methodology ofthe specific examples detailed hereinafter, e.g. the selection of moreoptimal reaction times and temperatures, as well as aid in the selectionof optimal processes.

The oxazolidine-2,4-diones of the present invention are readily adaptedto clinical use as antidiabetic agents. The hypoglycemic activityrequired for this clinical use is defined by the glucose tolerance testprocedure which follows. Intact male albino rats are the experimentaltest animals employed for such purposes. The test animals are fastedapproximately 18-24 hours. The rats are weighed, numbered and recordedin groups of five or six as needed. Each group of animals is then dosedintraperitoneally with glucose (one gram per kilogram) and orally witheither water (controls) or compound (at a level usually selected fromthe range 0.1 to 100 mg/kg). Blood glucose levels (mg/100 ml.) aremeasured in tail blood samples over a period of 3 hours in both controland treated groups. With equivalent zero hour blood glucose levels incontrol and treated groups, the % lowering of blood glucose at 0.5 hour,1 hour, 2 hours and 3 hours is calculated as: ##EQU1## Clinically usefulhypoglycemic agents show activity in this test. The hypoglycemicactivities determined for compounds of the present invention aresummarized in Table I. This table records % blood glucose lowering atthe 0.5 hour and 1 hour time points. A blood glucose lowering of 9% orgreater generally reflects statistically significant hypoglycemicactivity in this test. Those compounds which show significant activityonly at the 2 hour or 3 hour points have such activity recorded infootnotes.

                  TABLE I                                                         ______________________________________                                        Hypoglycemic Activity of Oxazolidine-2,4-Diones                               in the Rat Glucose Tolerance Test                                              ##STR15##      Dose       Blood Glucose Level% Lowering of                   Ar             (mg./kg.)  0.5 hr.   1 hr.                                     ______________________________________                                        8-Chromanyl    --         --        --                                        6-Chloro-      10         --        11                                        6-Fluoro-      10         --         9                                        2,3-Dihydrobenzo-furanyl                                                                     --         --        --                                        5-Chloro-      25         --        23 (a)                                    2-Pyrrolyl     100        11         8                                        1-Methyl-      100        18        17                                        1-Ethyl-       100        14        16                                        1-(1-Butyl)-   100         4        13                                        1-Phenyl       100        30        32                                        3-Indolyl      --         --        --                                        5-Bromo-       100         9        10                                        1-Methyl-      100        11         8                                        3-Pyridyl      --         --        --                                        2-Methoxy-     10         --        13                                        2-Ethoxy-      25         --        20                                        2-Methoxy-5-chloro-                                                                          25         22        17                                        2-Ethoxy-5-chloro-                                                                           10         --        24 (a)                                    5-Quinolyl     --         --        --                                        6-Methoxy-     20         --         7 (b)                                    8-Quinolyl     18         19        16                                        6-Chloro-      10         --        16                                        6-Fluoro-      10         --        15                                        7-Methoxy-     10         --        -- (c)                                    2-Thiazolyl-   75         11        10                                        2-Benzthiazolyl-                                                                             50          8        10                                        5-isoxazolyl   --         --        --                                        3-Methyl-      100         4         7 (d)                                    ______________________________________                                         (a) At 0.75 hour.                                                             (b) 9 at 2 hours.                                                             (c) 12 at 3 hours.                                                            (d) 24 at 2 hours, 14 at 3 hours.                                        

The oxazolidine-2,4-diones of the present invention are clinicallyadministered to mammals, including man, via either the oral or theparenteral route. Administration by the oral route is preferred, beingmore convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the patient cannot swallowthe medication, or absorption following oral administration is impaired,as by disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.10 to about 50 mg./kg. body weight of the subject per day,preferably about 0.20 to about 20 mg./kg. body weight per dayadministered singly or as a divided dose. However, the optimum dosagefor the individual subject being treated will be determined by theperson responsible for treatment, generally smaller doses beingadministered initially and thereafter increments made to determine themost suitable dosage. This will vary according to the particularcompound employed and with the subject being treated.

The compounds can be used in pharmaceutical preparations containing thecompound, or pharmaceutically acceptable acid salt thereof, incombination with a pharmaceutically acceptable carrier or diluent.Suitable pharmaceutically acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. The activecompound will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedabove. Thus, for oral administration the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions can if desired, contain additional components such asflavorants, sweeteners, excipients and the like. For parenteraladministration the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically acceptable acid addition salts of the compounds. Theinjectable solutions prepared in this manner can then be administeredintravenously, intraperitoneally, subcutaneously or intramuscularly,with intramuscular administration being preferred in man.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

EXAMPLE 1 Methyl 2-Methoxypyridine-3-carboxylate

Thionyl chloride (50 ml.) was added to 2-methoxypyridine-3-carboxylicacid (5 g.) in 50 ml. of carbon tetrachloride and the mixture refluxedfor 2 hours. The reaction mixture was cooled, evaporated to solids andchased with multiple portions of fresh carbon tetrachloride. Theresulting acid chloride hydrochloride was dissolved in excess methanol(50 ml.), stirred for 16 hours at room temperature, then evaporated anoil and taken up in chloroform. The chloroform solution was washed withtwo portions of saturated sodium bicarbonate and then one portion ofbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedto yield title product as an oil [4.63 g.; pnmr/CDCl₃ /delta (ppm): 3.9and 4.1 (2s, 6H), 6.9 (m, 1H), 8.2 (m, 2H)].

By the same procedure, 4-methylpyridine-3-carboxylic acid is convertedto methyl 4-methylpyridine-3-carboxylate.

EXAMPLE 2 3-Methanesulfinylmethylcarbonyl-2-Methoxypyridine

Sodium hydride (2.69 g., 50% dispersion in oil, 0.056 mole) was washedthree times with petroleum ether. Following the third decantation,traces of petroleum ether were removed by evaporation in vacuo.Dimethylsulfoxide (30 ml.) was added and the mixture heated in an oilbath at 75° C. for 45 minutes, by which time hydrogen evolution hadceased. The mixture was cooled in an ice-water bath and diluted with 30ml. of dry tetrahydrofuran. Title compound of the preceding Example(4.63 g., 0.028 mole) in 10 ml. of dry tetrahydrofuran was addeddropwise over 5 minutes. The reaction mixture was warmed and stirred atroom temperature for 30 minutes, poured into 180 ml. of water, acidifiedto pH 4 with 1N hydrochloric acid and extracted with three portions ofchloroform. The combined organic layers were dried over magnesiumsulfate, filtered and concentrated to yield title product as an oil[4.97 g.; pnmr/CDCl₃ /delta (ppm); 2.8 (s, 3H), 4.1 (s, 3H), 4.4 and 4.7(2d, 2H), 7.0 (m, 1H), 8.3 (m, 2H)].

By the same procedure the 4-methyl compound of the preceding Example isconverted to 3-methanesulfinylmethylcarbonyl-4-methylpyridine.

EXAMPLE 3 S-Methyl 2-Acetoxy-2-(2-methoxy-3-pyridyl)thioacetate

Title compound of the preceding Example (3.97 g.), sodium acetate (3.97g.) and acetic anhydride (40 ml.) were combined in 80 ml. of toluene andheated at 115° for 16 hours. The mixture was cooled and evaporated todryness in vacuo to yield crude product. The latter was chromatographedon 200 g. of silica gel with 2:1 chloroform:ethyl acetate as eluant, tlcmonitoring and collecting 10 ml. fractions. Clean product fractions58-79 were combined and concentrated to an oil. To remove possibletraces of residual acetic anhydride, the oil was taken into wet ethanol,held for 15 minutes, re-evaporated, chased with toluene, taken up inchloroform, dried over anhydrous magnesium sulfate, filtered, andre-evaporated to yield the title product as an oil [3.16 g.; Rf 0.60(3:1 ethyl acetate: methanol); m/e 255; ir (CH₂ Cl₂) 1748, 1686, 1582,1460, 1205 cm⁻¹ ].

By the same procedure the methyl compound of the preceding Example isconverted to S-methyl 2-acetoxy-2-(4-methyl-3-pyridyl)thioacetate.

EXAMPLE 4 5-(2-Methoxy-3-pyridyl)oxazolidine-2,4-dione

Sodium methoxide (632 mg., 11.7 mmoles) was taken into 50 ml. ofabsolute ethanol and the solution cooled in an ice-water bath. Urea (234mg., 3.9 mmole) was added, followed by the title compound of thepreceding Example (1.0 g., 3.9 mmole) in 5 ml. of ethanol. The mixturewas heated at reflux for 16 hours, then cooled to room temperature,neutralized with 11.7 ml. of 1N hydrochloric acid and evaporated to agum which was chased with toluene. The gum was chromatographed on 40 g.of silica gel with 1:2 ethyl acetate:chloroform as eluant, tlcmonitoring and 10 ml. fractions collected. Product containing fractions6-15 were combined and evaporated to a viscous oil, which wascrystallized from water [75 mg; m.p. 183°-186° C., Rf 0.32 (1:2 ethylacetate:chloroform)].

By the same method, the methyl analog of the preceding Example isconverted to 5-(4-methyl-3-pyridyl)oxazolidine-2,4-dione.

EXAMPLE 5 Ethyl 2-Ethoxypyridine-3-carboxylate

2-Ethoxypyridine-3-carboxylic acid (4 g.) was converted to its acidchloride hydrochloride by refluxing with 8.6 ml. of thionyl chloride for60 minutes. The reaction mixture was evaporated to solids with toluenechase to remove the excess thionyl chloride. The residue was taken into80 ml. of ethanol and held for 16 hours at 0° C., then evaporated tosolids, which were partitioned between toluene and 1N sodium hydroxide.The aqueous layer was extracted with fresh toluene and the two organiclayers combined, washed with water and then brine, dried over anhydrousmagnesium sulfate, filtered and evaporated to yield title product as anoil [3.2 g.; pnmr/CDCl₃ /delta (ppm) 1.6 (2s, 6H), 4.4-5.0 (2q, 4H), 7.2and 8.2 (m. 3H)].

EXAMPLE 6 2-Ethoxy-3-methanesulfinylmethyl carbonylpyridine

Using methylene chloride in place of chloroform in the isolation, theprocedure of Example 2 was employed to convert product of the precedingExample (3.0 g.) to title product [2.63 g.; m.p. 89°-91° C.; pnmr/CDCl₃/delta (ppm), 1.5 (t, 3H), 2.8 (s, 3H), 4.2-4.8 (s and q, 4H), 6.8-7.1and 8.0-8.4 (3H)].

EXAMPLE 7 S-Methyl 2-Acetoxy-2-(2-ethoxy-3-pyridyl)thioacetate

Using a reaction time of 4 hours at 100° C. and then 48 hours at roomtemperature, the procedure of Example 3 was employed to convert theproduct of the preceding Example (2.5 g.) to crude product, isolated asan oil by evaporation of the reaction mixture. The oil was taken up inethyl acetate, washed in sequence with three portions of 1N sodiumhydroxide, one of water and one of brine, dried over anhydrous magnesiumsulfate and evaporated to yield title product as an oil [2.96 g.; Rf0.78 (10:1 ethyl acetate:methanol); m/e 269].

EXAMPLE 8 2-(2-Ethoxy-3-pyridyl)-2-hydroxyacetamide

Product of the preceding Example (2.9 g.) was combined with 30 ml. ofethanol and 30 ml. of conc. ammonium hydroxide, stirred at roomtemperature for 3 hours and then evaporated to yield crude product as anoil (2.7 g.). The oil was chromatographed on 170 g. of silica gel usingethyl acetate as eluant and tlc monitoring. Clean product fractions werecombined and evaporated to yield title product as an oil [0.9 g.; Rf 0.6(10:1 ethyl acetate:methanol); pnmr/CDCl₃ /delta (ppm) 1.4 (t, 3H), 4.5(q, 2H), 5.4 (s, 1H), 6.2-8.2 (m, 5H)].

EXAMPLE 9 5-(2-Ethoxy-3-pyridyl)oxazolidine-2,4-dione

Product of the preceding Example (900 mg., 4.6 mmole) was combined with25 ml. of tert-butanol. Dimethyl carbonate (1.08 g., 9.2 mmole) and thenpotassium tert-butoxide (1.03 g., 9.2 mmole) were added and the reactionmixture refluxed for 3.5 hours. The reaction mixture was cooled, pouredinto 10 ml. of 1N hydrochloric hydrochloric acid, the pH adjusted to7.0, and extracted with two portions of ethyl acetate. The aqueous layerwas saturated with salt and extracted with additional ethyl acetate. Thethree organic layers were combined, back-washed with a small portion ofwater and then brine, dried over anhydrous magnesium sulfate andevaporated to yield crude product as a viscous oil. Purified titleproduct was obtained by crystallization from toluene (295 mg., m.p.140°-143° C.; m/e 272).

Anal. Calcd. for: C₁₀ H₁₀ O₄ N₂ :

C, 54.05; H, 4.54; N, 12.61.

Found: C, 54.34, H, 4.85, N, 12.70.

EXAMPLE 10 Methyl 5-Chloro-2-methoxypyridine-3-carboxylate

By the procedure of Example 1, 5-chloro-2-methoxypyridine-3-carboxylicacid [Sarges et al., J. Med. Chem. 19, 709 (1976); 10 g.] was convertedto its acid chloride, which was added in one portion to 150 ml. ofmethanol (slight exotherm), then made basic with triethylamine(approximately 1.1 equivalents). The reaction mixture was evaporated tosolids and the residue partitioned between ethyl acetate and water. Theethyl acetate layer was washed with fresh water and then brine, driedover anhydrous magnesium sulfate, filtered and evaporated to yield titleproduct [9.75 g., m.p. 79°-81° C.; pnmr/CDCl₃ /delta (ppm) 3.8 (s, 3H),4.1 (s, 3H), 8.1 (d, 1H), 8.3 (d, 1H)].

EXAMPLE 11 5-Chloro-3-methanesulfinylmethylcarbonyl-2-methoxypyridine

By the procedure of Example 2, the product of the preceding Example (9.7g., 0.045 mole) was converted to title product isolated as a visous oil(10.3 g., m/e 249/247).

EXAMPLE 12 S-Methyl2-Acetoxy-2-(5-chloro-2-methoxy-3-pyridyl)thioacetate

Using a reaction time of 19 hours at 100° C., the procedure of Example 3and the isolation method of Example 7 were employed to convert productof the preceding Example (10.3 g.) to title product in the form of aviscous oil (8.8 g.; pnmr/CDCl₃ includes singlet at 6.4; m/e 291/289).

EXAMPLE 13 2-(5-Chloro-2-methoxy-3-pyridyl)-2-hydroxyacetamide

Methanol (125 ml.) was saturated with anhydrous ammonia at 0°-5° C. Theproduct of the preceding Example (8.8 g.) in 25 ml. of methanol wasadded and the reaction mixture stirred overnight at room temperature,then concentrated to a viscous oil (7.3 g.). The oil was chromatographedon 400 g. of silica gel using 1:1 chloroform:ethyl acetate as eluant,tlc monitoring and 10 ml. fractions. Clean product fractions 190-270were combined and evaporated to yield title product [1.3 g.; m.p.110°-113° C.; m/e 218/216; ir(KBr) 3444, 3410, 1684 cm⁻¹ ].

EXAMPLE 14 5-(5-Chloro-2-methoxy-3-pyridyl)oxazolidine-2,4-dione

Using a reflux period of 15 hours, the procedure of Example 9 wasemployed to convert the product of the preceding Example (1.25 g., 5.8mmoles) to title product. To isolate, the reaction mixture was cooled toroom temperature and the pH adjusted to 3 with 1N hydrochloric acid. Themixture was then evaporated in vacuo to slightly gummy solids, whichgave filterable, crude product on stirring with 25 ml. of water (1.09g., m.p. 199°-204° C. Recrystallization from 15 ml. of ethanol gavepurified title product [470 mg.; m.p. 212°-214° C.; m/e 244/242; ir(KBr)3174, 3074, 2980, 1830, 1752 cm⁻¹ ].

EXAMPLE 15 2-(6-Chloro-8-quinolyl)-2-hydroxyacetamide

Ethyl 2-(6-chloro-8-quinolyl)-2-hydroxyacetate (1.6 g.) in 300 ml. ofconc. ammonium hydroxide was heated to reflux. Since completedissolution did not result, the reaction mixture was cooled, dilutedwith 50 ml. of ethanol and reheated to reflux for 0.5 hour. The reactionmixture was concentrted to a volume of 100 ml., cooled slowly and a cropof title product (320 mg., m.p. 195°-198° C.) recovered by filtration.Additional product (145 mg). was recovered by concentration of themother liquor to 50 ml. and extraction into three portions of ethylacetate. The combined organic layers were washed with saturated sodiumbicarbonate, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness.

By the same procedure, ethyl2-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)-2-hydroxyacetate is convertedto ethyl 2-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)-2-hydroxyacetamide.

EXAMPLE 16 5-(6-Chloro-8-quinolyl)oxazolidine-2,4-dione

Potassium tert-butoxide (292 mg., 2.6 mmoles) was dissolved in 20 ml. oftert-butanol. Dimethyl carbonate (234 mg. 2.6 mmoles) and then titlecompound of the preceding Example (300 mg., 1.3 mmoles) were added. Thereaction mixture refluxed for 18 hours, then cooled to room temperature,adjusted to pH 3 with 1N hydrochloric acid and diluted with 1Nhydrochloric acid and ethyl acetate. The aqueous layer was washed withtwo additional portions of ethyl acetate. The organic layers werecombined, washed with two portions of fresh 1N hydrochloric acid andthen brine, dried over anhydrous magnesium sulfate, filtered andevaporated to an oil (130 mg.). Crystallization of the oil fromisopropyl ether gave purified title product [58 mg., m.p. 207°-210° C.;ir(KBr) 1839, 1825, 1740 cm⁻¹ ].

By the same procedure the benzofuran analog of the preceding Example isconverted to5-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)oxazolidine-2,4-dione.

EXAMPLE 17 2-(6-Fluoro-8-quinolyl)-2-hydroxyacetamide

Ethyl 2-(6-fluoro-8-quinolyl)-2-hydroxyacetate (1.1 g.) was refluxed for10 minutes in 300 ml. of conc. ammonium hydroxide. The reaction mixturewas cooled slightly, clarified by filtration and evaporated to solids.Trituration of the residue with 25 ml. of toluene gave the title product(860 mg., m.p. 169°-171° C.).

EXAMPLE 18 5-(6-Fluoro-8-quinolyl)oxazolidine-2,4-dione

Using a reflux period of 3.5 hours, the product of the preceding Example(840 mg., 3.8 mmoles) was converted to title product by the procedure ofExample 16. In this case, a pH of 2 was used in the isolation withoutaddition of excess 1N hydrochloric acid and the crude product wasrecrystallized from toluene [120 mg., m.p. 202°-204° C.; m/e 246;ir(KBr) 1819, 1743, 1363 cm⁻¹ ].

EXAMPLE 19 5-(8-Quinolyl)oxazolidin-4-one-2-thione

Potassium thiocyanate (484 mg., 4.9 mmoles) and potassium cyanide (370mg., 5.7 mmoles) were combined in 5 ml. of water and cooled to 0° C.Quinoline-8-carbaldehyde [J. Org. Chem. 41, p. 957 (1976); 779 mg., 4.9mmoles] was added, followed by the dropwise addition of hydrochloricacid (30%, 1.9 ml.). After stirring for 25 minutes at 0° C., thereaction mixture was heated to 90°-100° C. for 25 minutes, cooled,quenched into crushed ice, adjusted to pH 8 with sodium bicarbonate andextracted with cloroform. The organic layer was dried over anhydrousmagnesium sulfate, filtered and evaporated to dryness (163 mg.). Thelatter was partitioned between 1N sodium hydroxide and ethyl acetate.The basic layer was acidified and extracted with fresh ethyl acetate.The two ethyl acetate layers were combined, dried, filtered andevaporated to yield title product [72 mg.; Rf 0.65 (ethyl acetate)]. Theoriginal, pH 8 aqueous layer was salted and extracted with ethyl acetateto yield an additional crop (114 mg.). The last aqueous phase wasacidified and extracted with ethyl acetate to yield a third crop (115mg.).

By the same method, 7-chloroquinoline-8-carbaldehyde is converted to5-(7-chloro-8-quinolyl)oxazolidin-4-one-2-thione.

EXAMPLE 20 5-(8-Quinolyl)oxazolidine-2,4-dione

Title compound of the preceding Example (230 mg., 0.94 mmole) was takeninto 6 ml. of 2:1 methanol:water and cooled to 0° C. Bromine (0.07 ml.,21.7 mg., 2.7 mmoles) was added and the reaction mixture allowed to warmslowly to room temperature, then stirred for 1 hour. The reactionmixture was evaporated to dryness and the residue partitioned between 1Nsodium hydroxide and ethyl acetate. The aqueous layer was separated,acidified and extracted with two portions of fresh ethyl acetate. Theacidic extracts were combined, dried and evaporated to an oil (144 mg.).Crystallization from toluene-chloroform and recrystallization fromtoluene gave purified title product (40 mg., m/e 228).

Anal. Calcd. for: C₁₂ H₈ O₃ N₂.0.33H₂ O: C, 61.54; H, 3.70; N, 11.96.

Found: C, 61.50; H, 3.89; N, 11.52.

By the same method the chloro compound of the preceding Example isconverted to 5-(7-chloro-8-quinolyl)oxazolidine-2,4-dione.

EXAMPLE 21 5-(6-Methoxy-5-quinolyl)oxazolidin-4-one-2-thione

By the procedure of Example 19, 6-methoxyquinoline-5-carbaldehyde (0.77g.) was converted to title product. After quenching into ice, a firstcrop (190 mg.) was isolated by extraction into ethyl acetate, dryingover anhydrous magnesium sulfate and evaporation to dryness. A secondcrop (176 mg.) was isolated in like manner by adjusting the aqueousphase to pH 8 with bicarbonate and extracting with additional ethylacetate. Both crops had m/e 274. The second crop also had m/e 258,indicating contamination with the product of the next step.

EXAMPLE 22 5-(6-Methoxy-5-quinolyl)oxazolidine-2,4-dione

The combined product crops of the preceding Example (0.36 g., 1.31mmole) were taken into 15 ml. of methanol. Sodium metaperiodiate (0.56g., 2.62 mmoles) in 7.2 ml. of 5% sodium bicarbonate was added dropwise.After stirring for 3 hours at room temperature, the reaction mixture wasquenched with water, acidified and extracted with two portions of ethylacetate. The organic extracts were combined, dried over anhydrousmagnesium sulfate, filtered and evaporated to dryness (110 mg.). Theaqueous phase was adjusted to pH 7 and further crude product (100 mg.)obtained by extraction with ethyl acetate. The crude crops werecombined, taken into 1N sodium hydroxide, acidified to pH 4 with aceticacid and extracted with fresh ethyl acetate. The latter organic extractswere combined and evaporated to dryness. Trituration of the residue withether, allowing the mixture to stand until crystallization was complete,gave title product (34 mg.; m.p. 144°-146° C.).

EXAMPLE 23 5-(7-Methoxy-8-quinolyl)oxazolidin-4-one-2-thione

By the procedure of Example 19, but using adjustment to pH 7 withbicarbonate after quench and ethyl acetate for extraction,7-methoxyquinoline-8-carbaldehyde (2.0 g., 10.7 mmoles) was converted totitle product [1.17 g.; Rf 0.7 (2:1 ethyl acetate:chloroform)]Thisproduct was not partitioned between aqueous base and ethyl acetate, norwas a second crop isolated by salting the aqueous phase and furtherextracting.

EXAMPLE 24 5-(7-Methoxy-8-quinolyl)oxazolidine-2,4-dione

Product of the preceding Example (0.74 g., 2.7 mmoles) was combined with30 ml. of methanol and 15 ml. of 5% sodium bicarbonate. Sodiummetaperiodate (1.15 g., 5.4 mmoles) in 15 ml. of water was addeddropwise. After stirring for 3 hours at room temperature, the reactionmixture was quenched with water, acidified to pH 2-3 and extracted withtwo portions of ethyl acetate. The extracts were combined, dried andevaporated to dryness (360 mg.). Recrystallization from water gavepurified title product (100 mg.; m.p. 207°-208° C.).

Anal. Calcd. for C₁₃ H₉ N₂ O₃.1.2H₂ O:

C, 59.40; H, 4.34; N, 10.66.

Found: C, 59.33; H, 4.01; N, 10.66.

EXAMPLE 255-Hydroxy-5-(1-methyl-2-pyrrolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione

Alloxan hydrate (3.2 g., 0.02 mole) was dissolved in 50 ml. of ethanolby warming. 1-Methylpyrrole (1.6 g., 0.02 mole) was added and themixture warmed for 5 minutes on a steam bath, while perfusing withhydrogen chloride. After standing at room temperature for 0.5 hour, thereaction mixture was evaporated to dryness and the residue trituratedwith water to yield title product as a solid [2.9 g.; m/e 223; Rf 0.5(1:1 ethyl acetate:hexane/5% acetic acid)].

EXAMPLE 26 5-(1-Methyl-2-pyrrolyl)oxazolidine-2,4-dione

Product of the preceding Example (2.8 g.) was combined with 25 ml. of 1Nsodium hydroxide and heated on a steam bath for 30 minutes, by whichtime complete dissolution had occurred. On acidification, a gumprecipitated, which solidified on trituration with water (1.2 g.).Recrystallization from methanol-ether afforded purified title product[0.70 g.; m.p. 108-114 (dec); m/e 180].

Anal. Calcd. for C₈ H₈ O₃ N₂ : C, 53.33; H, 4.48; N, 15.55.

Found: C, 53.16; H, 4.72; N, 15.28.

EXAMPLE 275-Hydroxy-5-(1-ethyl-2-pyrrolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione

Potassium pyrrole [J. Chem. Soc., p. 52 (1931); 1 g.; 0.01 mole]wasslurried in 5 ml. of tetrahydrofuran. Ethyl iodide (1 ml., 0.012 mole)was added, a slight exotherm being noted. The mixture was stirred for0.5 hour, heated to reflux for 0.5 hour, cooled to room temperature,diluted with 15 ml. of water and extracted with 10 ml. of ether. Theether extract was washed with 5 ml. of water, then added to alloxanhydrate (1.6 g.) which had been dissolved in 25 ml. of ethanol byheating. The ether was boiled off and the ethanolic residue refluxed for0.5 hour, then evaporated to a water-soluble gum. The gum was taken upin 25 ml. of ethyl acetate, washed with two 10 ml. portions of water andre-evaporated to yield title product as a gum (0.6 g., m/e 237).

EXAMPLE 28 5-(1-Ethyl-2-pyrrolyl)oxazolidine-2,4-dione

The procedure of the preceding Example was repeated on a three timesscale. The initially isolated product gum (0.03 mole of thepyrimidinetrione) was stirred with 60 ml. of 1N sodium hydroxide for 0.5hour, then acidified with conc. hydrochloric acid and extracted withethyl acetate. The extract was filtered from insoluble impurities, andconcentrated to a gum (2.2 g.). The gum was chromatographed on 100 ml.of silica gel with (1:1 ethyl acetate:hexane as eluant and tlcmonitoring. Early fractions contained the desired product; these werecombined and evaporated to an oil which crystallized on standing.Trituration with water gave purified title product (170 mg.; m.p.90°-93° C.; m/e 194).

Anal. Calcd. for C₉ H₁₀ O₃ N₂.0.25H₂ O:

C, 54.40; H, 5.32; N, 14.10.

Found: C, 54.37; H, 5.16; N, 13.76.

EXAMPLE 29 5-Hydroxy-5-[1-(1-butyl)-2-pyrrolyl)

2,4,6-(1H,3H,5H)pyrimidinetrione

Potassium pyrrole (3.0 g., 0.03 mole), 1-iodobutane (9.2 g., 0.05 moles)and 10 ml. of tetrahydrofuran were combined and refluxed for 1.5 hoursby which time the reaction mixture had become a thick mass. The reactionmixture was diluted with 30 ml. of water and extracted with 35 ml. ofether. The ether was backwashed with water, then added to a solution ofanhydrous alloxan (4.8 g., 0.03 mole) obtained by heating in 50 ml. ofethanol. The ether was distilled away, 6N hydrochloric acid (5 ml., 0.03mole) was added, and the mixture refluxed for 3 minutes, cooled,evaporated to a gum, and triturated with water to afford title product[5.1 g.; m.p. 135 (dec); m/e 265].

EXAMPLE 30 5-[1-(1-Butyl)-2-purolyl]oxazolidine-2,4-dione

Product of the preceding Example (5.1 g., 0.019 mole) was combined with1N sodium hydroxide (38 ml., 0.038 mole) and stirred at room temperaturefor 10 minutes. The reaction mixture was filtered, washed with ether,cooled in an ice-water bath, acidified with conc. hydrochloric acid andextracted with three portions of ethyl acetate. The organic extractswere combined, washed with brine, dried over anhydrous sodium sulfateand evaporated to gummy solids. The latter was chromatographed on silicagel with ethyl acetate as eluant and tlc monitoring to yield partiallypurified product isolated as an oil (950 mg.). The latter wasrechromatographed using 1:1 ethyl acetate: hexane as eluant, yieldingpurified title product as an oil [0.59 g.; m/e 222; Rf 0.72 (ethylacetate)].

Anal. Calcd. for C₁₁ H₁₄ O₃ N₂.0.5H₂ O:

C, 57.38; H, 6.57; N, 12.17.

Found: C, 57.40; H, 6.35; N, 12.15.

EXAMPLE 31 Sodium 5-[1-(1-butyl)-2-pyrolyl]oxazolidine-2,4-dione

Product of the preceding Example (370 mg., 1.66 mmoles) was dissolved in5 ml. of methanol. Sodium bicarbonate (90 mg., 1.66 mmoles) was added.The resulting solution was evaporated to dryness and the solid residuetriturated with ether to yield the title product [300 mg.; m.p.123°-126° C. (dec); tlc mobility with 1:1 ethyl acetate:hexane/5% aceticacid as eluant identical with the free base form].

EXAMPLE 325-Hydroxy-5-(1-phenyl-2-pyrrolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione

1-Phenylpyrrole (1.4 g., 0.01 mole), alloxan hydrate (1.6 g., 0.01 mole)and 50 ml. of ethanol were combined and refluxed for 15 minutes. Noreaction was noted by tlc. 1N Hydrochloric acid (10 ml., 0.01 mole) wasadded and the acidified mixture refluxed for 15 minutes. Incompletereaction was noted by tlc. A second portion of alloxan hydrate (1.6 g.,0.01 mole) was added and the mixture refluxed another 15 minutes, cooledand evaporated to dryness. Trituration of the residue with water gavetitle product [2.3 g.; m/e 285; m.p. 232°-234° C. (dec); Rf 0.3 (1:1ethyl acetate:hexane)].

Anal. Calcd. for C₁₄ H₁₁ O₄ N₃.0.25H₂ O:

C, 58.01; H, 4.00; N, 14.50.

Found: C, 57.84; H, 4.05; N, 14.56.

EXAMPLE 33 5-(1-Phenyl-2-pyrrolyl)oxazolidine-2,4-dione

The product of the preceding Example (1 g.) was heated on a steam bathfor 20 minutes with 20 ml. of 1N sodium hydroxide. The mixture was thencooled in an ice-water bath, acidified with conc. hydrochloric acid andthe supernatant decanted from the resulting gummy precipitate. The gumwas taken up in ethyl acetate, washed with water, and evaporated to anoil (0.47 g.). The aqueous decant was also extracted with ethyl acetate,the extract back washed with water and evaporated to a second oil (0.28g.). The two oils were combined, chromatographed on 150 ml. of silicagel with 1:1 ethyl acetate:hexane as eluant and tlc monitoring. Theearly, product fractions were combined, evaporated to an oil (410 mg.)and the oil crystallized from ether-hexane to yield purified titleproduct [280 mg.; m.p. 130°-132° C.; m/e 242; Rf 0.47 (1:1 ethylacetate: hexane)].

Anal. Calcd. for C₁₃ H₁₀ O₃ N₂ : C, 64.46; H, 4.16; N, 11.57.

Found: C, 64.40; H, 4.35; N, 11.56.

EXAMPLE 345-Hydroxy-5-(1-methyl-3-indolyl)-2,4,6,-(1H,3H,5H)pyrimidinetrione

Alloxan hydrate (1.6 g., 0.01 mole) 1-methylindole (1.3 g., 0.01 mole)and ethanol (50 ml.) were combined and the mixture refluxed for 0.5hour, then concentrated to half-volume, diluted with water and theresulting product recovered by filtration [2.7 g., Rf 0.5 (1:1 ethylacetate:hexane/5% acetic acid)].

EXAMPLE 35 5-(1-Methyl-3-indolyl)oxazolidine-2,4-dione

Product of the preceding Example (2 g.) was heated on a steam bath for15 minutes with 35 ml. of 1N sodium hydroxide. The reaction mixture wascooled to room temperature, acidified to pH 1 with conc. hydrochloricacid, and decanted from a small amount of gum (130 mg.). The decant wasclarified by filtration, cooled in an ice-water bath, and the resultingsolids (330 mg.) recovered by filtration. The filtrate was extractedwith ethyl acetate; the extract was back-washed with water andevaporated to solids (0.61 g.). The solid products were combined andrecrystallized from ethyl acetate/hexane to yield title product (0.33g.; m.p. 152°-153.5° C.).

Anal. Calcd. for C₁₂ H₁₀ O₃ N₂.0.125H₂ O:

C, 61.99; H, 4.45; N, 12.05.

Found: C, 61.99; H, 4.45; N, 12.02.

EXAMPLE 365-Hydroxy-5-(5-bromo-3-indolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione

Alloxan hydrate (1.6 g., 0.01 mole) was dissolved in 40 ml. of ethanolby heating. 5-Bromoindole (1.96 g., 0.01 mole) was added and heatingnear reflux continued for 15 minutes. Tlc did not indicate that reactionhad occured. 1N Hydrochloric acid (10 ml.) was then added whilemaintaining the reaction near reflux. After 10 minutes, the reaction wasconcentrated to wet solids. Trituration of these wet solids with watergave the title product [3.17 g., m.p. >250° C.; Rf 0.45 (1:1 ethylacetate:hexane/5% acetic acid); Rf 0.3 (1:5 ethyl acetate:hexane/5%acetic acid)].

EXAMPLE 37 5-(5-Bromo-3-indolyl)oxazolidine-2,4-dione

Product of the preceding Example (3.1 g.) was heated on a steam bathwith 50 ml. of 1N sodium hydroxide for 15 minutes, then cooled and crudeproduct (1.25 g.) precipitated by acidification with conc. hydrochloricacid. Chromatography on silica gel, using 1:1 ethyl acetate:hexane aseluant and tlc monitoring gave purified title product [0.41 g.; m.p.185°-189° C.; Rf 0.55 (1:5 ethyl acetate:hexane/5% acetic acid)].

Anal. Calcd. for C₁₁ H₇ O₃ N₂ Br: C, 44.76; H, 2.38; N, 9.49.

Found: C, 45.10; H, 2.68; N, 9.58.

EXAMPLE 38 5-Hydroxy-5-(2-thiazolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione

Thiazole (1.7 g., 0.02 mole) was dissolved in tetrahydrofuran (35 ml.)and cooled to -60° C. Butyllithium (9 ml. of 2.4M in hexane, 0.0216mole) was added dropwise over 20 minutes, and the reaction mixturestirred for an additional 30 minutes at -60° C. In this manner2-thiazolyllithium was formed. Anhydrous alloxan (3 g., 0.021 mole) wasdissolved in 20 ml. of tetrahydrofuran and added dropwise over 20minutes, keeping the temperature at -60° C. The stirred reaction mixturewas warmed to room temperature over 30 minutes, then recooled to 0° C.1N Hydrochloric acid (25 ml.) was added portion wise and the quenchedreaction mixture extracted with 50 ml. of ethyl acetate. The ethylacetate extract was back-washed with 15 ml. of water, dried overanhydrous sodium sulfate, filtered and evaporated to yield title product[1.9 g.; m/e 227; Rf 0.4 (1:1 ethyl acetate:hexane/5% acetic acid)].

By the same procedure, oxazole is converted to5-hydroxy-5-(2-oxazolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione.

EXAMPLE 39 5-(2-Thiazolyl)oxazolidine-2,4-dione

Title product of the preceding Example (1.37 g.) was stirred at roomtemperature with 24 ml. of 1N sodium hydroxide. The reaction mixture wasallowed to stand for 25 minutes, acidified with 3 ml. of glacial aceticacid and extracted with two 50 ml. portions of ethyl acetate. Theextracts were separately dried over sodium sulfate, filtered andevaporated to solids, the first yielding 184 mg., the second 85 mg.These solids were combined and chromatographed on 50 ml. of silica gelwith 1:1 ethyl acetate:hexane/5% acetic acid as eluant and tlcmonitoring. Clean product fractions were combined, evaporated to drynessand the residue triturated with hexane to yield purified title product(155 mg.; m.p. 150°-152° C.).

Anal. Calcd. for C₆ H₄ O₃ N₂ S: C, 39.13; H, 2.19; N, 15.21.

Found: C, 39.53; H, 2.52; N, 14.95.

By the same procedure, the other product of the preceding Example isconverted to 5-(2-oxazolyl)oxazolidine-2,4-dione.

EXAMPLE 405-Hydroxy-5-(2-benzthiazolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione

By the procedure of Example 38, benzthiazole (2.7 g., 0.02 moles) wasconverted to its 2-lithio derivative and then reacted with anhydrousalloxan to yield title product, initially isolated as an oil. The latterwas crystallized from ether-hexane [2.2 g.; Rf 0.55 (1:1 ethylacetate:hexane/5% acetic acid)].

EXAMPLE 41 5-(2-Benzthiazolyl)oxazolidine-2,4-dione

Product of the preceding Example 2.15 g.) was stirred with 30 ml. of 1Nsodium hydroxide for 30 minutes. The reaction mixture was extracted withether and product (0.46 g.) precipitated by acidification of the aqueouslayer with 6N hydrochloric acid. Chromatography on 50 ml. of silica gelwith 1:1 ethyl acetate: hexane/5% acetic acid as eluant and tlcmonitoring, followed by recrystallization from acetone-isopropyl ethergave purified title product [110 mg., m.p. 214216° C. (dec)].

Anal. Calcd. for C₁₀ H₆ O₃ N₂ S: C, 51.29; H, 2.58; N, 11.96

Found: C, 51.51; H, 2.99; N, 12.21.

EXAMPLE 42 2-(6-Chloro-8-chromanyl)-2-trimethylsiloxy-ethanenitrile

6-Chlorochroman-8-carbaldehyde (7 g., 0.036 mole) in 70 ml. of methylenechloride was cooled to 0°-5° C. Zinc iodide (100 mg.) was added,followed by the dropwise addition of trimethylsilylcarbonitrile (4.26g., 0.043 mole). The reaction mixture was stirred at room temperaturefor 64 hours, then washed in sequence with three portions of saturatedsodium bicarbonate and one of brine, dried over anhydrous magnesiumsulfate, filtered and evaporated to yield title product as an oil [9.5g.; ir(CH₂ Cl₂) 2857, 1479, 1215, 1190, 1060 cm⁻¹ ].

EXAMPLE 43 Ethyl 1-(6-Chloro-8-chromanyl)-1-hydroxymethanecarboximidateHydrochloride

To cold (0°-5° C.), saturated ethanolic hydrogen chloride (250 ml.)there was added, in a dropwise manner, product of the preceding Example(9.29 g.) in 15 ml. of ethanol, keeping the temperature below 10° C. Themixture was stirred at 0°-5° C. for 35 minutes and then evaporated to anoil. Crystallization from ethanolether gave title product [5.7 g.; m.p.125°-127° (dec); m/e 271/269].

EXAMPLE 44 5-(6-Chloro-8-chromanyl)oxazolidine-2,4-dione

Product of the preceding Example (5.4 g., 18.6 mmoles) was suspended in250 ml. of tetrahydrofuran, cooled in an ice-water bath, andtriethylamine (6.01 g., 0.06 mole) added. The cold mixture was perfusedwith phosgene for 30 minutes, stirred at room temperature for 1 hour andthen poured into 1 liter of crushed ice. The quenched reaction mixturewas extracted with three portions of methylene chloride. The combinedextracts were washed with brine, dried over anhydrous magnesium sulfateand evaporated to solids. The residue was recrystallized from toluene toyield purified title product (3.28 g., m.p. 170°-172° C., m/e 269/267).

Anal. Calcd. for C₁₂ H₁₀ O₄ NCl: C, 53.84; H, 3.77; N, 5.23

Found: C, 53.73; H, 3.83; N, 5.48.

EXAMPLE 45 2-(6-Fluoro-8-chromanyl)-2-trimethylsiloxyethanenitrile

By the procedure of Example 42, 6-fluorochroman-8-carbaldehyde (3.2 g.,0.0178 mole) was converted to title product as an oil [4.51 g., m/e 279;ir (CHCl₂) 1498, 1205, 1066 cm⁻¹ ].

EXAMPLE 46 Ethyl 1-(6-Fluoro-8-chromanyl)-1-hydroxymethanecarboximidateHydrochloride

Using a reaction time of 1 hour at 0°-5° C., the procedure of Example 43was employed to convert product of the preceding Example (4.4 g.) totitle product [4.1 g.; m.p. 124°-126° C. (dec); m/e 253].

EXAMPLE 47 5-(6-Fluoro-8-chromanyl)oxazolidine-2,4-dione

By the procedure of Example 44, product of the preceding Example (3.9g., 0.0134 mole) was converted to crude title product. Crude solids weretaken into 1N sodium hydroxide and extracted with two portions of ether.Product was reprecipitated by adding the basic aqueous layer slowly toexcess 3N hydrochloric acid. Recrystallization from toluene gavepurified title product [2.73 g.; m.p. 174°-176° C.; m/e 251].

Anal. Calcd. for C₁₂ H₁₀ O₄ NF: C, 57.37; H, 4.01; N, 5.58.

Found: C, 57.74; H, 3.91; N, 5.40.

EXAMPLE 482-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)-2-trimethylsiloxyethanenitrile

5-Chloro-2,3-dihydrobenzo[b]furan-7-carbaldehyde (900 mg., 4.9 mmoles)was dissolved in 25 ml. of ether. Zinc iodide (20 mg.) and thentrimethylsilylcarbonitrile (970 mg., 9.8 mmoles) were added and themixture stirred 16 hours at room temperature, then diluted with 50 ml.ether, washed with three portions of saturated sodium bicarbonate andone of brine, dried over anhydrous magnesium sulfate, filtered andevaporated to yield title product as an oil [1.4 g.; m/e 283/281;ir(CHCl₂) 1479, 1457, 1435, 1180, 866, 848 cm⁻¹ ].

By the same method 5-fluoro-2,3-dihydrobenzo[b]furan-7-carbaldehyde isconverted to2-(5-fluoro-2,3-dihydro-7-benzo[b]furanyl)-2-trimethylsiloxyethanenitrile.

EXAMPLE 49 Ethyl1-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)-1-hydroxymethanecarboximidateHydrochloride

By the procedure of Example 43, title compound of the preceding Example(1.37 g.) was converted to title product. The initially isolated solidswere repulped twice in ether to obtain purified product [1.28 g.; m.p.149°-152° C. (dec); m/e 257/255; ir(KBr) 3162, 2875, 1650, 1524, 1458cm⁻¹ ].

By the same method the fluoro compound of the preceding Example isconverted to ethyl1-(5-fluoro-2,3-dihydro-7-benzo[b]furanyl)-1-hydroxymethanecarboximidatehydrochloride.

EXAMPLE 505-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)oxazolidine-2,4-dione By theprocedure of Example 44, title compound of the preceding Example (1.1g.) was converted to toluene recrystallized title product [630 mg.; m.p.197°-199° C.; m/e 255/253; ir(KBr) 3084, 1833, 1810, 1746 cm⁻¹ ].

By the same procedure the fluoro analog of the preceding Example isconverted to5-(5-fluoro-2,3-dihydro-7-benzo[b]furanyl)oxazolidine-2,4-dione.

EXAMPLE 51 2-(3-Methyl-5-isoxazolyl)-2-trimethylsilylethanenitrile

By the procedure of Example 42, 3-methylisoxazole-5-carbaldehyde (3.4g., 0.032 mole) was converted to title product, isolated as an oil (6.5g., no aldehyde proton by nmr).

By the same method, isothiazole-5-carbaldehyde is converted to2-(5-thiazolyl)-2-trimethylsilylethanenitrile and5-methylisoxazole-3-carbaldehyde (Kane et al., Japan 62/17,572) isconverted to 2-(5-methyl-3-isoxazolyl)-2-trimethylsilylethanenitrile.

EXAMPLE 52 Ethyl 1-Hydroxy-1-(3-methyl-5-isoxazolyl)methanecarboximidateHydrochloride

Title product of the preceding Example (6.5 g.) was dissolved in cold,saturated ethanolic hydrogen chloride (50 ml.) and held at 5° C. for 16hours. Title product was recovered by filtration (3.3 g., m.p. 119°-121°C.).

By the same method, the other products of the preceding Example areconverted to ethyl 1-hydroxy-1-(5-isothiazolyl)methanecarboximidatehydrochloride and ethyl1-hydroxy-1-(5-methyl-3-isoxazolyl)methanecarboximidate hydrochloride.

EXAMPLE 53 5-(3-Methyl-5-isoxazolyl)oxazolidine-2,4-dione

By the procedure of Example 44, title product of the preceding Example(2.2 g.), was converted to title product. After quench into crushed ice,the product was extracted into ether, the combined extracts dried andevaporated to an oil (1.4 g.). Further extraction with ethyl acetate andevaporation gave additional oil (0.4 g.). The oils were combined andpartitioned between 25 ml. of 1N sodium hydroxide and 25 ml. of ether.The basic aqueous phase was separated, acidified with conc. hydrochloricacid and extraced with 25 ml. of ethyl acetate. The ethyl acetateextract was back-washed with water, evaporated to dryness, the residuetriturated with ether (146 mg., m.p. 173°-175° C.). The ether trituratewas evaporated to dryness and triturated with fresh ether (238 mg., m.p.175°-177° C.).

By the same method, the other products of the preceding Example areconverted to 5-(5-isothiazolyl)oxazolidine-2,4-dione and5-(5-methyl-3-isoxazolyl)oxazolidine-2,4-dione.

EXAMPLE 54 5-(5-Chloro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione

5-(2-Ethoxy-3-pyridyl)oxazolidine-2,4-dione (125 mg.) was suspended in100 ml. of water and dissolved by warming to 56° C. Chlorine was bubbledinto the warm solution for 30 minutes, during which time the temperatureslowly dropped to 34° C. and a precipitate formed. The reaction mixturewas flushed with nitrogen for 30 minutes and crude product recovered byfiltration (101 mg., m.p. 119°-124° C.). Two recrystallizations from 2:1ethanol:water gave purified title product [24 mg.; m.p. 145°-147° C.; Rf0.56 (1:1 ethyl acetate: chloroform); m/e 256].

By the same procedure, substituting 10% fluorine in nitrogen,5-(2-ethoxy-3-pyridyl)oxazolidine-2,4-dione is converted to5-(5-fluoro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione.

PREPARATION 1 2-Ethoxy-3-pyridinecarboxylic Acid

Sodium ethoxide was prepared by adding sodium (1.4 g., 0.06 mole)portion wise to 50 ml. of anhydrous ethanol. The solution was dilutedwith 20 ml. of ethanol and 4.5 g. of 2-chloropyridine-3-carboxylic wasadded. The reaction mixture was heated in a steel pressure vessel at170° C. for 6 hours. The vessel was cooled and the contents evaporatedto dryness in vacuo. The residue was taken up in 150 ml. of water andacidified to constant pH 4.5. The water solution was saturated with saltand extracted with four portions of ethyl acetate. The combined ethylacetate layers were back washed with brine, dried over anhydrousmagnesium sulfate, filtered and evaporated to yield title product (4.33g., m.p. 85°-88° C.).

PREPARATION 2 2-Methoxy-3-pyridinecarboxylic Acid

A stainless steel stirred autoclave was charged sequentially withmethanol (2.8 1.), sodium methoxide (259 g.) (in portions, keeping thetemperature less than 35° C.), and 2-chloro-3-pyridinecarboxylic acid(190 g.). The autoclave was sealed and the reaction mixture heated at110° C. (50 psig) for 48 hours. The reaction mixture was cooled to 25°C. and discharged from the autoclave. Solids were recovered byfiltration. Concentration of the filtrate gave a second crop. Theseprocess steps were repeated until virtually all of the methanol had beenremoved. The several crops of solids were combined, taken up in 2.5liters of water and midified with conc. hydrochloric acid to pH 2.7keeping the temperature below 20° C. The precipitated product wasgranulated for 30 minutes at 15° C. and recovered by filtration (141g.). Purified title product was obtained by recrystallization from ethylacetate-hexane (120.5 g., m.p. 148°-150° C.).

PREPARATION 3 Ethyl 2-(6-Chloro-8-quinolyl)-2-oxoacetate

8-Bromo-6-chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g.,0.025 mole]in 50 ml. of tetrahydrofuran was added dropwise over a 10minute period to a mixture of butyl lithium (2.3M in hexane, 12.2 ml.,0.028 mole) and 40 ml. of tetrahydrofuran held at -70° C. After anadditional 30 minutes at this temperature, a cold (0° C.) solution ofdiethyl oxalate (14.6 g., 0.10 mole) in 50 ml. of tetrahydrofuran wasadded dropwise. The reaction mixture was maintained at 0° C. for 1 hour,then quenched at 0°-5° C. with glacial acetic acid (17 ml.) in 50 ml. oftetrahydrofuran. After warming to room temperature the quenched mixturewas poured into 500 ml. of water and then diluted with 500 ml. of ethylacetate and 500 ml. of saturated sodium bicarbonate. The organic layerwas separated, washed with 500 ml. of fresh bicarbonate, dried overanhydrous magnesium sulfate, filtered, and evaporated to an oil.Trituration with two 100 ml. portions of hexane gave the title product(2.3 g., m.p. 107°-110° C.; m/e 265/263).

PREPARATION 4 Ethyl 2-(6-Chloro-8-quinolyl)-2-hydroxyacetate

Sodium borohydride (2.5 g., 0.066 mole) was dissolved in 300 ml. ofethanol at 10° C. and added in one portion to a 10° C. solution ofproduct of the preceding Preparation (2.0 g., 0.0076 mole) in 200 ml. ofethanol. After a few minutes, the reaction mixture was diluted with 750ml. of ethyl acetate and 750 ml. of water. The aqueous layer wasextracted with 250 ml. of fresh ethyl acetate. The organic layers werecombined, washed with three 250 ml. portions of brine, dried overanhydrous magnesium sulfate, filtered and evaporated to yield titleproduct, initially an oil which crystallized on standing (1.87 g.; m.p.121°-124° C., m/e 267/265).

PREPARATION 5 Ethyl 2-(6-Fluoro-8-quinolyl)-2-oxoacetate

By the procedure of Preparation 3, 8-bromo-6-fluoroquinoline [J. Het.Chem., 6, pp. 243-245 (1969); 4.5 g., 0.02 mole] was converted to hexanetriturated title product (1.6 g.; m.p. 114°-117° C.).

PREPARATION 6 Ethyl 2-(6-Fluoro-8-quinolyl)-2-hydroxyacetate

By the procedure of Preparation 4, product of the preceding Preparation(1.5 g., 6.1 mmoles) was converted to title product. The product,initially obtained as a turbid oil, was taken back up in ethyl acetate,washed with brine, dried, filtered and evaporated to an oil whichrapidly crystallized (1.23 g., m.p. 84°-87° C.).

PREPARATION 7 6-Hydroxyquinoline-5-carbaldehyde

Sodium hydroxide (25 g.) was dissolved in 35 ml. of water with cooling,6-hydroxyquinoline (5 g.) in 15 ml. of chloroform was added and thereaction mixture heated to reflux (about 90° C.) for 12 hours, duringwhich two further 15 ml. portions of chloroform were added--one after 2hours and the other after 6 hours. The reaction mixture was cooled andcrude product recovered by filtration. The crude was dissolved in 125ml. of hot water treated with activated carbon, filtered hot, cooled andacidified with acetic acid and filtered to yield title product [2.5 g.;m.p. 136°-137° C.; m/e 173; pnmr/CDCl₃ shows aldehyde proton at 10.5 ppmand aromatic protons at 7.2-9.4 ppm.].

PREPARATION 8 6-Methoxyquinoline-5-carbaldehyde

Product of the preceding Preparation (1.7 g., 9.8 mmoles) in 85 ml. ofacetone was combined with potassium carbonate (1.21 g., 8.8 mmoles).Dimethyl sulfate (0.83 ml., 8.8 mmoles) was added and the mixturestirred at room temperature for 16 hours. Additional potassium carbonate(0.34 g., 2.5 mmole) and methyl sulfate (0.23 ml., 2.5 mmole) were addedand the mixture stirred 4 more hours at room temperature and then 3hours at 60° C. The reaction mixture was cooled to room temperature,salts removed by filtration, and the filtrate evaporated to dryness. Theresidue was taken up in ethyl acetate, washed sequentially with twoportions of 1N ammonium hydroxide, one of water and one of brine, driedover anhydrous magnesium sulfate, filtered and evaporated to yield titleproduct [0.78 g.; Rf 0.35 (2:1 ethyl acetate:chloroform); pnmr/CDCl₃/delta (ppm): 4.2 (s, 3H), 7.4-9.1 (m, 5H), 10.3 (s, 1H)].

PREPARATION 9 7-Hydroxyquinoline-8-carbaldehyde

By the procedure of the Preparation 7, 7-hydroxyquinoline (5 g.) wasconverted to title product (3.3 g., m.p. 127°-130° C.; m/e 173;pnmr/CDCl₃ shows aldehyde proton at 10.8 ppm, aromatic protons at7.0-8.9 ppm.

PREPARATION 10 7-Methoxyquinoline-8-carbaldehyde By the procedure ofPreparation 8, the product of the preceding Preparation (3.3 g., 19mmoles) was converted to title product [2.1 g., pnmr/CDCl₃ /delta (ppm):4.1 (s, 3H), 7.5-9.0 (m, 5H), 11.2 (s, 1H)]. PREPARATION 116-Chlorochroman

Mossy zinc (75 g.), 7.5 g. of mercuric chloride, 125 ml. of water and 4ml. of conc. hydrochloric acid were combined, shaken for 5 minutes,allowed to settle, and liquids decanted from the resulting amalgamatedzinc. A mixture of 100 ml. of water and 126 ml. of conc. hydrochloricacid and then 6-chloro-4-chomanone (15 g.) were added to the metal, andthe mixture refluxed for 1.5 hours, cooled to room temperature, decantedfrom the zinc and the decant extracted with three portions of ether. Thecombined extracts were dried over anhydrous magnesium sulfate, filteredand concentrated to an oil (14 g.). The oil was chromatographed on 400g. of silica gel using 9:1 hexane: ether as eluant tlc monitoring and 15ml. fractions. Clean product fractions were combined and evaporated toyield title product as an oil [8.72 g.; pnmr/CDCl₃ /delta (ppm) 2.0 (m,2H), 3.7 (t, 2H), 4.1 (t, 2H), 6.9 (m, 3H); m/e 170/168; Rf 0.88 (2:1hexane: ether)].

PREPARATION 12 6-Chlorochroman-8-carbaldehyde

Product of the preceding Preparation (8.6 g., 0.051 mole) in 75 ml. ofmethylene chloride was cooled in an ice-water bath. Titaniumtetrachloride (19.34 g., 11.2 ml., 0.102 mole) was added, followed bythe dropwise addition of 1,1-dichloromethyl methyl ether (6.2 g., 0.054mole). The reaction mixture was stirred at 0° for 30 minutes, thenslowly poured into 400 ml. of saturated sodium bicarbonate. The aqueousphase was extracted with three fresh portions of methylene chloride. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered and evaporated to yield title product [7.9g.; m.p. 83°-86° C.; pnmr/CDCl₃ /delta (ppm) 2.0 (m, 2H), 2.8 (t, 2H),4.2 (t, 2H), 7.1-7.5 (m, 2H), 10.2 (s, 1H), m/e 198/196].

PREPARATION 13 6-Fluorochroman

By the procedures of Preparation 11, 6-fluoro-4-chromanone (15 g.) wasconverted to chromatographed 6-fluorochroman [5.7 g.; oil; pnmr/CDCl₃/delta (ppm) 2.0 (m, 2H), 3.8 (t, 2H), 4.1 (t, 2H), 6.8 (m, 3H); Rf 0.68(2:1 hexane:ether); m/e 152].

PREPARATION 14 6-Fluorochroman-8-carbaldehyde

By the procedures of Preparation 12, the product of the precedingPreparation (5.5 g., 0.036 mole) was converted to title productinitially isolated as a viscous oil which was crystallized from hexane(3.4 g.; m.p. 54°-57° C.; m/e 180).

PREPARATION 15 3-Methyl-5-isoxazolecarboxamide

3-Methyl-5-isoxazolecarboxylic acid (20 g.) was refluxed for 10 hours in350 ml. of thionyl chloride, then stirred at room temperature for 16hours, clarified by filtration and evaporated to an oil. The oil wasmultiply triturated with hot hexane, and the combined hexane trituratesevaporated to yield acid chloride (16.2 to 21 g.) as a solid.

With stirring, acid chloride prepared in the manner (35 g.) was addedportionwise to 300 ml. of conc. ammonium hydroxide at room temperature.After granulating for 1 hour, title product was recovered by filtration(24.2 g., m.p. 180°-182° C.).

PREPARATION 16 3-Methyl-5-isoxazolecarbonitrile

Product of the preceding Preparation (5 g.) was mixed thoroughly withphosphorous pentoxide (10 g.) and placed in an oil bath preheated to140° . The bath temperature was increased to 200° C. and title productrecovered by distillation in vacuo [2.9 g., ir(film) nitrile band at2220 cm¹, no amide peak in the 1700 cm⁻¹ region].

PREPARATION 17 3-Methyl-5-isoxazolecarbaldehyde

Product of the preceding Preparation (1.08 g., 0.01 mole) was dissolvedin 25 ml. of ether and cooled to -40° C. Diisobutylaluminum hydride (12ml. of 1M in hexane, 0.012 mole) was added at -40° C. over a 15 minuteperiod. The mixture was stirred at -30° to -35° C. for 10 minutes.Keeping the temperature at -20° C., 60 ml. of ethyl acetate was added.Keeping the temperature at -25° C., methanol (15 ml.) was addeddropwise, and keeping the temperature below -20° C., 3 ml. of 6Nhydrochloric acid was added. The reaction mixture was warmed to 5° C.and the organic phase washed with 25 ml. of water and evaporated to anoil. The oil was chromatographed on 50 ml. of silica gel using 1:1ether:hexane as eluant. Product fractions were combined and evaporatedto yield title product (0.42 g.; m.p. 39°-41° C.). A small samplefurther purified by sublimation had m.p. 43°-45° C.

PREPARATION 18 5-Chlorobenzo[b]furan-2 carboxylic Acid

5-Chlorosalicylaldehyde (31.3 g., 0.2 mole) was dissolved in 200 ml. of2-butanone. Potassium carbonate (82.9 g., 0.6 mole) and then diethyl2-bromomalonate (95.6 g., 0.4 mole) were added and the mixture heated toreflux for five hours, then cooled, filtered from salts, andconcentrated to an oil. The oil was partitioned between 500 ml. of 10%sulfuric acid and 500 ml. of ether. The aqueous layer was extracted withtwo 250 ml. portions of fresh ether. The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated to a second oil. The second oil was dissolved in 400 ml. of10% ethanolic potassium hydroxide, heated at reflux for 1 hour andconcentrated to solids. The solids were dissolved in 1500 ml. of water,filtered from trace insoluble matter, acidified with 6N hydrochloricacid and precipitated solids recovered by filtration. Purified titleproduct was obtained by repulping the solids in 1 liter of water (19 g.,m.p. 259°-262° C., m/e 198/196).

By the same procedure, 5-fluorosalicyaldehyde and6-chlorosalicylaldehyde are converted, respectively, to5-fluorobenzo[b]furan-2-carboxylic acid and6-chlorobenzo[b]furan-2-carboxylic acid.

PREPARATION 19 5-Chlorobenzo[b]furan

Title compound of the preceding Preparation (7.8 g.) was combined withcopper powder (700 mg.) and quinoline (50 ml.) and the mixture heated toreflux for 50 minutes, then cooled to room temperature and diluted with500 ml. of ether. Insolubles were removed by filtration and the filtratewashed in sequence with five 200 ml. portions of 2N hydrochloric acidand one of brine, dried over anhydrous magnesium sulfate andconcentrated to an oil (6.2 g.). The oil was chromatographed through 200g. of silica gel using ether as eluant and 300 ml. fractions. Fractions1 and 2 were combined and evaporated to yield title product as an oil(6.1 g.).

By the same procedure the other benzofurancarboxylic acids of thepreceding Preparation are converted to 5-fluorobenzo[b]furan and6-chlorobenzo[b]furan.

PREPARATION 20 5-Chloro-2,3-dihydrobenzo[b]furan

Pd/C (5%, 12.2 g.) in 400 ml. of acetic acid was prehydrogenated atatmospheric pressure and 25° C. Title compound of the precedingPreparation (6.1 g.) in 100 ml. of acetic acid was added andhydrogenation continued until slightly more than 1 equivalent ofhydrogen had been consumed. Catalyst was recovered by filtration overdiatomaceous earth. The filtrate was neutralized with saturatedpotassium carbonate and extracted with four 200 ml. portions of ether.The combined extracts were washed with brine, dried over anhydrousmagnesium sulfate, filtered and evaporated to an oil. The oil waschromatographed on 400 g. silica gel using hexane-3% ether as eluant, 15ml. fractions and tlc monitoring. Pure product fractions 70-90 werecombined and evaporated to yield title product [2.15 g.; oil; Rf 0.32(hexane); m/e 156/154].

By the same procedure, the other benzofurans of the precedingPreparation are converted to 5-fluoro2,3-dihydrobenzo[b]furan and6-chloro-2,3-dihydrobenzo[b]furan.

PREPARATION 21 5-Chloro-2,3-dihydrobenzo[b]furan-7-carbaldehyde

By the procedure of Preparation 12, title compound of the precedingPreparation (2.1 g.) was converted to crude product contaminated with anisomeric aldehyde. Purified title product was obtained by digesting thecrude product in 50 ml. of boiling hexane, filtering and cooling thefiltrate [0.93 g.; m.p. 79°-81° C.; Rf 0.55 (chloroform); m/e 184/182].

By the same method the 5-fluoro compound of the preceding Preparation isconverted to 5-fluoro-2,3-dihydrobenzo[b]furan-7-carbaldehyde.

By the method of Preparation 3, the 6-chloro compound is converted toethyl 2-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)-2-oxoacetate; then bythe method of Preparation 4 to ethyl2-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)-2-hydroxyacetate.

PREPARATION 22 7-Chloroquinoline-8-carbaldehyde

7-Chloro-8-methylquinoline (1 g.) [Bradford et al., J. Chem. Soc., p.437 (1947)]is dissolved in 20 ml. of benzene and brominated with oneequivalent of N-bromosuccinimide in the presence of catalytic amounts ofperoxide. The product, 7-chloro-8-(bromomethyl)quinoline is isolated byevaporation.

The bromo compound is solvolyzed to 7-chloro-8-(hydroxymethyl)quinolineby warming with excess alcoholic potassium hydroxide. To isolate theproduct, the reaction mixture is neutralized with hydrochloric acid,salts separated by filtration and the filtrate evaporated to dryness.

The alcohol (1 g.) is dissolved in 10 ml. of methylene chloride andadded dropwise to a slurry of 1.5 equivalents of pyridinumchlorochromate in 20 ml. of methylene chloride. The exothermic reactionis controlled by rate of addition, use of a reflux condenser andoccasional cooling in a cooling bath. The reaction mixture is dilutedwith ether, and the supernatant separated by decantation and filtration.The product is purified by filtration through a short magnesium silicatecolumn with ether as eluant and isolated by removal of the solvent invacuo.

I claim:
 1. A compound of the formula ##STR16## or a pharmaceuticallyacceptable salt thereof, wherein R is hydrogen, (C₁ -C₄)-alkanoyl,benzoyl, (C₂ -C₄)carbalkoxy, (C₁ -C₃)-alkylcarbamoyl (C₅-C₇)-cycloalkylcarbamoyl or di(C₁ -C₃)-alkylcarbamoyl;Q is sulfur oroxygen; and V is hydrogen or (C₁ -C₃)alkyl.
 2. A compound of claim 1wherein R is hydrogen and Q is sulfur.
 3. The compound of claim 2 havingthe formula ##STR17##
 4. The compound of claim 2 having the formula##STR18##
 5. A method of lowering the blood glucose in a hyperglycemicmammal which comprises administering a blood glucose lowering amount ofa compound of claim 1.